Camilla Pegoraro, Ekaterina Karpova, Yusuf Qutbuddin, Esther Masiá Sanchis, Pavels Dimitrijevs, Cristián Huck‐Iriart, Svetozar Gavrilović, Pavel Arsenyan, Petra Schwille, Carles Felip‐León, Aroa Duro‐Castano, Inmaculada Conejos‐Sanchez, María J. Vicent
{"title":"Polyproline‐Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism","authors":"Camilla Pegoraro, Ekaterina Karpova, Yusuf Qutbuddin, Esther Masiá Sanchis, Pavels Dimitrijevs, Cristián Huck‐Iriart, Svetozar Gavrilović, Pavel Arsenyan, Petra Schwille, Carles Felip‐León, Aroa Duro‐Castano, Inmaculada Conejos‐Sanchez, María J. Vicent","doi":"10.1002/adma.202411595","DOIUrl":null,"url":null,"abstract":"Mitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and/or present inefficient/insufficient cytosolic delivery (resulting in poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis/characterization of polypeptide‐based cell penetrating diblock copolymers of poly‐L‐ornithine (PLO) and polyproline (PLP) (PLO<jats:sub>n</jats:sub>‐PLP<jats:sub>m</jats:sub>, n:m ratio 1:3) are described as mitochondria‐targeting nanocarriers. Synthesis involves a simple two‐step methodology based on N‐carboxyanhydride ring‐opening polymerization, with the scale‐up optimization using a “design of experiments” approach. The molecular mechanisms behind targetability and therapeutic activity are investigated through physical/biological processes for diblock copolymers themselves or as targeting moieties in a poly‐L‐glutamic (PGA)‐based conjugate. Diblock copolymers prompt rapid cell entry via energy‐independent mechanisms and recognize mitochondria through the mitochondria‐specific phospholipid cardiolipin (CL). Stimuli‐driven conditions and mitochondria polarization dynamics, which decrease efficacy depending on disease type/stage, do not compromise diblock copolymer uptake/targetability. Diblock copolymers exhibit inherent concentration‐dependent anti‐tumorigenic activity at the mitochondrial level. The diblock copolymer conjugate possesses improved safety, significant cell penetration, and mitochondrial accumulation via cardiolipin recognition. These findings may support the development of efficient and safe mitochondrial‐targeting nanomedicines.","PeriodicalId":114,"journal":{"name":"Advanced Materials","volume":"82 1","pages":""},"PeriodicalIF":27.4000,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advanced Materials","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1002/adma.202411595","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Mitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and/or present inefficient/insufficient cytosolic delivery (resulting in poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis/characterization of polypeptide‐based cell penetrating diblock copolymers of poly‐L‐ornithine (PLO) and polyproline (PLP) (PLOn‐PLPm, n:m ratio 1:3) are described as mitochondria‐targeting nanocarriers. Synthesis involves a simple two‐step methodology based on N‐carboxyanhydride ring‐opening polymerization, with the scale‐up optimization using a “design of experiments” approach. The molecular mechanisms behind targetability and therapeutic activity are investigated through physical/biological processes for diblock copolymers themselves or as targeting moieties in a poly‐L‐glutamic (PGA)‐based conjugate. Diblock copolymers prompt rapid cell entry via energy‐independent mechanisms and recognize mitochondria through the mitochondria‐specific phospholipid cardiolipin (CL). Stimuli‐driven conditions and mitochondria polarization dynamics, which decrease efficacy depending on disease type/stage, do not compromise diblock copolymer uptake/targetability. Diblock copolymers exhibit inherent concentration‐dependent anti‐tumorigenic activity at the mitochondrial level. The diblock copolymer conjugate possesses improved safety, significant cell penetration, and mitochondrial accumulation via cardiolipin recognition. These findings may support the development of efficient and safe mitochondrial‐targeting nanomedicines.
期刊介绍:
Advanced Materials, one of the world's most prestigious journals and the foundation of the Advanced portfolio, is the home of choice for best-in-class materials science for more than 30 years. Following this fast-growing and interdisciplinary field, we are considering and publishing the most important discoveries on any and all materials from materials scientists, chemists, physicists, engineers as well as health and life scientists and bringing you the latest results and trends in modern materials-related research every week.